CR2 (CD21) is a 145 kD membrane glycoprotein present on the surface of mature B cells. It is the receptor for C3dg, a proteolytic fragment of the third component of complement (C3), as well as the receptor for gp350/220, a surface glycoprotein of the Epstein-Barr virus. CR2 may have several functions in the control of the immune response. It can serve to enhance the binding of immune complexes or other complement-activating antigens to B lymphocytes. This would, in theory, increase the ability of B cells to present these antigens to T lymphocytes. Alternatively, ligation of CR2 may desensitize B cells by transmembrane signaling linked to CD19. The objective of this study is to clarify the role that CR2 may have in the regulation of the immune response: 1. Are C3 fragments generated by an in vitro model of physiologic complement activation able to participate in antigen binding and internalization by CR2? 2. Will binding of such antigens augment their presentation to MHC class II-restricted T cells? 3. What is the role of intercellular adhesion molecules in the presentation of antigen by cells expressing CR2? 4. Can synthetic ligands for CR2 serve to modulate the immune response? The cDNA for CR2 has been transfected into cells of the human fibroblast line, M1, that have previously been transfected with DNA encoding HLA-DR1. These cells will serve as antigen presenting cells (APC) for a panel of antigen specific T cell clones restricted by HLA-DR1. The antigen (UV-inactivated influenza virus) will be delivered to the APC directly or as immune complexes coated with complement. The cellular biology of CR2-mediated antigen uptake will be investigated using immuno-fluorescent and electron microscopy. Mutants of CR2 lacking key functional domains will be studied for their ability to influence antigen presentation. Lastly, a series of potential immunomodulators derived from C3dg or CR2 will be used to either augment or inhibit class Il-restricted antigen presentation by the M1 cells. These include viral antigens conjugated to peptides having the known CR2-binding motif, peptides derived from C3dg or the CR2 sequence itself to block binding, or a soluble form of CR2. These experiments will lend insight into mechanisms of antigen processing, the role of CR2 in the immune response, and potential therapeutics for autoimmune or infectious diseases.